Cancer Literature Review

Finding solutions to cancer – World Cancer Day 2020

Diamond Light Source is playing its part in reducing the global impact of cancer and supporting the aims of World Cancer Day. Research taking place at Diamond is improving our understanding of cancer mechanisms and producing new opportunities for effective cancer therapies.

Over the past two years Diamond has published over 345 publications related to cancer research, covering numerous cancer types and many basic research studies on the structure of cancer cells and pathways. A particular focus has been utilising the immune system to become more efficient in targeting cancer cells and designing new targeted therapies.

New approaches to cancer therapy

The limitations of chemotherapy and radiotherapy have driven a search for novel ways to prevent and treat cancers. Research teams from around the world have been using Diamond’s world-leading facilities to investigate many new approaches, some of which are described below.

Cancer cells have developed mechanisms to protect themselves from being destroyed by a body’s immune system. Researchers around the world are looking at different ways to overcome these complex mechanisms. An international team of researchers has been investigating the role of the immune receptor Tim-3 and its related protein galectin-9 in shielding breast cancer cells. They found that breast tumours express significantly higher levels of Tim-3 and galectin-9 than healthy tissue. The team partnered with Diamond scientists and used synchrotron radiation circular dichroism spectroscopy on the B23 beamline to investigate these defence mechanisms. The research also revealed increased levels of these key proteins in nine other cancers, highlighting the important role of the Tim-3-galectin-9 pathway in cancer development. Further research is required to discover the best way to disable the pathway to allow the immune system to attack cancer cells.

Another promising new approach to cancer therapy is the use of monoclonal antibodies (mAbs) to modulate the immune response and improve the body’s ability to destroy cancer cells. To date however use of anti-4-1BB mAbs such as urelumab has been limited due to intolerable side-effects. An international team redesigned a 4-1BB molecule to form a recombinant antibody called a trimerbody that had potent stimulatory activity with no associated toxicity. They used High Throughput Small Angle X ray Scattering (SAXS) on beamline B21 as part of their research. This novel approach may unlock the potential of immunotherapeutic antibodies in the treatment of cancer with minimal side-effects.

The cyclin-dependent protein kinase (CDK) family are involved in the regulation of the cell cycle and in differentiating cell types. Dysregulation of their activity is associated with inappropriate cell cycle progression and cancer, and so CDKs have been studied intensively as potential anti-cancer targets in certain cancer subtypes. The first generation of these molecules had dose-limiting toxicities. A team of researchers from Newcastle Cancer Centre used macromolecular crystallography techniques on beamlines I03, I04-1 and I04 to distinguish subtle yet profound differences between different CDK sub-types that may allow the unusual properties of CDK1 inhibitors to be used as anti-cancer therapies.

Bromo and extra-terminal (BET) proteins play an important role in cell transcription and such have become attractive pharmaceutical targets in the fight against cancer. A team of researchers from Canadian institutions and Oxford University performed a range of systematic proteomics, biophysical, structural, and cell biological studies, including macromolecular crystallography on beamlines I02, I03 and I24. These studies provided a framework to better understand BET biochemistry and promote the rational development of new inhibitors.

P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures have been defined, these are either at low resolution, or represent mutated and/or quiescent states of the protein. A study from the University of Manchester using the Titan Krios-I electron microscope in the Electron Bioimaging Centre (eBIC) at Diamond defined new high resolution features of ABCB1 at 8 Angstrom which provided valuable insights into the mechanism of drug stimulation of P-glycoprotein activity. This in turn will aid in the future design of an effective and reversible P-glycoprotein inhibitor to address multi-drug resistance in cancer therapy.

The protein Mcl-1 (myeloid cell leukaemia 1) is associated with cancers of high tumour grade, poor survival and resistance to chemotherapy, and has emerged as an attractive target for cancer therapy. Overexpression of Mcl-1 has been reported in a variety of haematological malignancies and solid tumours and research in this area may apply to a wide range of cancers. An international pharmaceutical company research group screened a large number of promising compounds to identify selective small molecule inhibitors of Mcl-1 using nuclear magnetic resonance and X-ray derived structural information.

Crystallography was performed on beamlines I03 and I04 at Diamond. These early research efforts have identified a lead compound that is currently undergoing further analysis. Another recent study on Mcl-1 discovered and characterised an antibody fragment produced in vitro which could be used in future cancer treatment. The study used macromolecular crystallography on beamlines I02, I03, I04 and I04-1 to crystallize the antibody fragment with Mcl-1 enabling ligand-independent crystallization. This early research was vital in supporting the discovery of a new compound AZD5991 which is currently in clinical trials for treating relapsed chronic lymphocytic leukaemia and multiple myeloma.

The hunt for a universal cancer vaccine

Therapeutic vaccination against tumour-associated antigens (TAA) has been a highly anticipated approach where a patient’s own immune system is boosted to treat cancer, in particular harnessing the anti-cancer potential of CD8 cytotoxic T-lymphocytes. However, to date results with universal cancer vaccines have been largely disappointing. A team from the Universities of Cardiff and Copenhagen identified and refined super-agonist altered peptide ligands (APLs)from the blood of healthy donors and were also able to induce T-cells from the blood of patients with melanoma. Among other methods, the team used macromolecular crystallography on beamline I24 to generate the peptide structures. These APLs were capable of inducing T-cells with greater effectiveness and suggest that this could be a promising approach in the hunt for a universal cancer vaccine.

Tackling triple negative breast cancer

A diagnosis of triple negative (TN) breast cancer means that the tumour does not have the three most common types of receptor that promotes tumour growth. Common therapies for this cancer type are therefore ineffective and patients have a poor prognosis. Efforts are being made to design new therapies and researchers are looking at the capability of viruses to deliver effective therapies. Viruses are extremely efficient vectors for intracellular delivery, but attempts to use them to treat disease has been associated with undesirable side-effects including mortality in some cases. Recently, much safer synthetic analogues for viruses have been developed. A research group from the University of Sheffield has designed synthetic Dengue virus-mimicking nanoparticles to target TN breast cancer.

The team were able to selectively target TN breast cancer cells and show that genetic material can be efficiently delivered to the cell nuclei while maintaining high cell viability. They used small angle X-ray scattering and diffraction (SAXS) analysis on beamline I22 to accurately characterise the nanoparticles. This work shows potential for new therapeutic approaches for the treatment of TN breast cancer.

New hope in treating pancreatic cancer

Pancreatic cancer is a particularly difficult cancer to treat and currently has no effective therapies.Pancreatic ductal adenocarcinoma (PDA) is difficult-to-treat cancer characterised by immune tolerance and resistance to immunotherapies including T-cell checkpoint-based immunotherapy which is becoming the standard of care for a number of cancers. A team of US researchers discovered upregulation of the protein kinase RIP1 in tumour-associated macrophages in PDA and suggested it could be a promising target in PDA. They developed a selective small-molecule RIP1 inhibitor and used macromolecular crystallography on beamline I02 to show that RIP1 inhibition is protective against PDA in vivo. The team suggested that RIP1 could be regarded as an immune checkpoint kinase and their research supports RIP1 inhibition as a potential new therapeutic avenue in the treatment of PDA.

Another international study investigated a number of new compounds for their anti-pancreatic cancer activity. The team focused their attention on discoidin domain receptors (DDRs) which are members of the tyrosine kinase family. Dysregulation of DDR1 is involved in several cellular processes including cell differentiation and adhesion, and is often detected in cancer. The crystallographic structure of DDR1 was determined on beamline I04 and the team designed and used a DDR1 inhibitor to successfully slow pancreatic cancer progression and to improve sensitivity to standard of care pancreatic cancer therapies. DDR1 is now being considered as a novel target for drug discovery against pancreatic cancer.

Developing non-invasive diagnosis of prostate cancer

Zinc concentration is a known biomarker for prostate cancer and is markedly reduced in cancer while remaining high in benign conditions. Until recently zinc concentration could only be measured using a tissue biopsy, but a research team from the University of Texas has been exploring non-invasive imaging methods using magnetic resonance imaging (MRI) and synchotron radiation X-ray fluourescence (µSR-XRF). They used a zinc responsive contrast agent to detect zinc release in the prostate in a mouse model and confirmed that zinc concentration was associated with the presence of malignant tissue. The team worked on beamline I18 during the study and highlighted the advantage of using MRI to characterise the distribution and trafficking of zinc in healthy and malignant prostate tissue. These initial studies may provide an important way forward for the early diagnosis and treatment of prostate disease.

Understanding the Epstein Barr virus portal

The Epstein-Barr virus, which belongs to the herpesvirus family, is one of the most widespread human viruses and the main cause of infectious mononucleosis (also known as glandular fever). In addition, it causes several kinds of cancer, including Burkitt and Hodgkin’s lymphoma, stomach cancer and nasopharyngeal cancer, as well as several autoimmune diseases. There is currently no treatment for infections caused by this virus.

An international team of researchers studied the structure of a key protein in the virus known as a portal which is the entrance and exit point for the viral genome. The team solved the structure of the portal at 3.5 Angstrom resolution using the Titan Krios I electron microscope in the eBIC at Diamond. The detailed architecture of this protein suggests that it plays a functional role in DNA retention during packaging. New understanding of the portal structure paves the way for the rational design of inhibitors for the treatment of cancers.

A new approach to non-small cell lung cancer

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. An industry research group used a structure-based design approach which included use of macromolecular crystallography on beamline I04 to identify appropriate ERK1/ERK2 inhibitors. The research led to the identification of AZD0364, a potent and selective ERK1/2 inhibitor which prevents activation of ERK1/2 and inhibits activation of downstream targets. The compound exhibits high cellular potency and good physico-chemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging anti-tumour activity in pre-clinical models of non-small cell lung cancer. Clinical trials on this new compound are planned to commence in the near future.

Read more about the latest research from Diamond in our Science Highlights.

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